Oral delivery product

ABSTRACT

An oral delivery product comprises a semi-permeable pouch designed for being placed in the oral cavity of a subject. The pouch encloses multiple solid particles of an alginate salt of monovalent cation comprising a biologically active substance comprised in the matrix formed by the alginate salt in the particles.

TECHNICAL FIELD

The present invention generally relates to oral delivery of activeagents, and in particular to an oral delivery product in the form of anoral pouch.

BACKGROUND

There are many ways of delivering active pharmaceutical agents to apatient body depending on the type of drug and the disorder to treat orprevent. A common administration protocol is oral delivery of oralformulations, such as tablets, capsules and lozenges. In thisadministration route, the tablet is swallowed for release of the agentin the intestine.

A problem associated with oral delivery to the stomach is that manydrugs may be degraded during the passage through the acid environment ofthe gastrointestinal system. When the agent has entered the intestine itis taken up into the blood stream via the portal vein in the liver,where a large portion of the active agent is typically metabolized intoinactive chemicals by the enzymes of the so-called first-passmetabolism.

These factors result in a significant delay before a positivetherapeutic effect can be noted, leading to a risk of gastrointestinalside effects augmented by the need of administering considerably higheramount of the active agent than would be needed by, for instance, adirect injection of a drug solution into the vein.

WO 2007/104573 discloses the delivery of the active agent nicotine tothe oral cavity of a patient in the form of a snuff product. The snuffproduct comprises a semi-permeable snuff pouch enclosing small particlesof microcrystalline cellulose having the nicotine sorbed to the surfaceof the cellulose particles.

When being placed between the lip and the teeth of the patient, theonset of the nicotine effect is very rapid, typically within 1 to 2minutes after application of the snuff pouch.

WO 2005/023227 discloses nicotine-containing pharmaceutical compositionswherein nicotine is absorbed into and/or adsorbed onto cellulose ofnon-seed organism origin, especially cellulose from algae, bacteriaand/or fungi. A vast amount of products comprising the pharmaceuticalcompositions are given in the document, including chewing gums, mouthsprays, nasal sprays, inhaling devices, tablets, lozenges, buccalsachets, transdermal patches and powders.

SUMMARY

The nicotine molecules present on the surface of the cellulose particlesare exposed to a potentially harsh environment. For instance, ambientoxygen may oxidize the exposed nicotine into, among others,nicotine-N-oxide. Furthermore, several of the additives suggested in WO2007/104573 and WO 2005/023227, in particular, color and flavoringagents can be quite reactive, thereby negatively affecting the nicotinebound to the cellulose particle surface.

The present invention overcomes these and other drawbacks of the priorart arrangements.

It is a general objective to provide an efficient oral delivery product.

It is a particular objective according to an embodiment to provide anoral delivery product that can be used as a smoke or snuff curingproduct.

Briefly, the present invention involves an oral delivery productcomprising a semi-permeable pouch designed for being placeable in anoral cavity of a subject, preferably mammalian subject and morepreferably a human subject. The pouch is preferably constructed to beplaceable under the lip and between the lip and the teeth of a humansubject in similarity to a wet snuff pouch or bag.

The semi-permeable pouch encloses and comprises multiple solid particlesof at least one alginate salt of monovalent cation. These alginateparticles further comprise at least one biologically active substancewithin the matrix formed by the alginate molecules of the particles.

When being placed in the oral cavity of the subject the moisturenaturally present in the mouth causes a gradual dissolution of thealginate particles and a delivery of the at least one biologicallyactive substance entrapped therein. The so released at least onebiologically active substance can achieve a local biological, includingtherapeutic, effect in the oral cavity or, preferably, a systembiological effect in the subject by being systemically taken up throughthe mucous membranes in the mouth.

The semi-permeable pouch can comprise a single alginate salt speciesachieving a fast or prolonged substance delivery depending on theparticular molecular weight and viscosity of the alginate salt. Amixture of different alginate salt species can also be used to achieve acontrolled release according to a desired delivery profile by mixingalginate molecules of different molecular weights and viscosities.

The alginate matrix of the multiple solid particles efficiently protectsthe at least one biologically active substance contained therein duringthe shelf life of the product. Furthermore, a controlled localenvironment, added to meet stability requirements, administrationrequirements and/or effect efficiency of the at least one biologicallyactive substance, can be achieved through the inclusion of selectedadditives in the alginate matrices.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention together with further objects and advantages thereof, maybest be understood by making reference to the following descriptiontaken together with the accompanying drawings, in which:

FIGS. 1A and 1B illustrate a view from above and a side view of anembodiment of an oral delivery product;

FIG. 2 illustrates a view from above of another embodiment of an oraldelivery product;

FIG. 3 is a flow diagram illustrating a method of producing an oraldelivery product according to an embodiment;

FIG. 4 is a flow diagram illustrating additional, optional steps of theproducing method in FIG. 3;

FIG. 5 is a flow diagram illustrating an embodiment of the forming stepin FIG. 3;

FIG. 6 is a flow diagram illustrating another embodiment of the formingstep in FIG. 3; and

FIG. 7 is a schematic diagram of serum concentration of an active agentversus time using an embodiment of the oral delivery product.

DETAILED DESCRIPTION

Throughout the drawings, the same reference characters will be used forcorresponding or similar elements.

The present embodiments relate to an oral delivery product that can beused for achieving a controlled release of a biologically activesubstance to an animal, preferably a mammalian and more preferably ahuman being.

The oral delivery product of the invention is designed for being placedin the oral cavity of the animal, preferably in contact with the mucousmembrane of the oral cavity. The product is based on providing multiplesolid particles carrying the biologically active substance within amatrix formed by the particles.

These matrix-forming particles not only work as a carrier of the activesubstance but also provide a controlled, local environment within thematrix for the biologically active substance. As a consequence, the oraldelivery product can advantageously be used in connection withbiologically active substances requiring a certain local environment forachieving its biologically effect, for being efficiently taken up in theanimal body and/or protecting the biologically active substance fromdegradation and other reactive substances that might be present in theoral cavity or indeed in the oral delivery product.

The oral delivery product is based on the usage of at least one alginatesalt. Alginate, the salt of alginic acid, is a linear polysaccharidenaturally produced by brown seaweeds (Phaeonphyceae, includingLaminaria). Alginate is composed of multiple monomer residues, typically100 to 3 000 monomers, linked together in a flexible chain. Theseresidues are mainly of β-(1→4)-linked D-mannuronic acid (M) residues andβ-(1→4)-linked L-guluronic acid (G) residues. These two residues areepimers and only differ at C5. In the polymer chain, they though giverise to very different conformations with any two D-mannuronic acidresidues being ⁴C₁-diequatorially linked while the link connecting anyto L-guluronic acid residues is a ¹C₄-diaxial link as is illustrated informula I:

The residues are generally organized in blocks of identical or strictlyalternating residues, e.g. MMMMMM . . . , GGGGGG . . . , or GMGMGM . . ..

The alginate polymers form, in the presence of monovalent cations,dissolvable solid particles. This is in clear contrast to the case, whenthe alginate polymers are instead in contact with divalent cations, suchas Ca²⁺. The divalent cations form links between different alginatepolymers to thereby achieve cross-linking between the alginate polymers.The cross-linking in turn leads to the formation of an alginate filmthat is generally not dissolvable or at least difficult to dissolve inmoist environments.

Suitable monovalent cations that can be used in the present embodimentsinclude sodium ions (Na⁺), potassium ions (K⁺) and ammonium ions (NH₄⁺), preferably Na⁺.

Solid alginate particles can be formed from an aqueous solution of thealginate polymers in the presence of at least one monovalent cation.These solid particles form and enclose a matrix presenting asubstantially isolated environment. This means that the particles arevery suitable as carriers for biologically active substances to beadministered in a controlled release process and in particular sensitiveactive substances or substances requiring a certain local environmentfor achieving an efficient administration and uptake and/or preventingdegradation or undesired reactions to the active substances.

The embodiments therefore present solid particles of at least onealginate salt of monovalent cation forming a matrix, in which at leastone biologically active substance is contained. These multiple solidparticles carrying the biologically active substance or substances arein turn enclosed in a semi-permeable pouch to form the oral deliveryproduct. The oral delivery product is therefore designed to generally beused in a similar way as a traditional snuff bag or pouch in that thedelivery product achieves its substance administration by being placedin the oral cavity of a subject. The semi-permeable pouch preferably hasan overall size and design for allowing it to be effectively placed inthe intended place of the oral cavity, preferably under the lip andbetween the lip and the teeth of the subject. The actual dimensions ofthe semi-permeable pouch can non-inventively be determined by the personskilled in the art based on the anatomy of the intended subject animal.Thus, for human subjects, the semi-permeable pouch preferably has a sizesimilar to the snuff pouches and bags that are presently used in thetobacco market today.

The semi-permeable pouch may be of any suitable material, includingwoven or non-woven fabric, such as cotton, fleece, etc., heat sealablenon-woven cellulose or other polymeric materials, such as synthetic,semi-synthetic or natural polymeric material, including hydrophilic orhydrophobic materials. Examples of suitable materials are celluloseacetate and derivates thereof, carboxymethyl cellulose, polycelluloseester, other cellulose derivates including ethylcellulose andpropylcellulose, polyethylene, polypropylene, polystyrene, polyvinylchloride, polyvinyl acetate, polymers of methacrylates and acrylates,natural rubber, polycarbonate, polyethylene terephtalate, polyester,polyamide and nylon.

In a preferred embodiment, the material of the semi-permeable pouch isnot dissolvable or at least difficult to dissolve when being placed inthe oral cavity of the subject. Thus, following administration of thebiologically active substance enclosed by the alginate particles presentin the pouch, the pouch with any remaining enclosed material is removedfrom the oral cavity and is discarded.

The pouch is semi-permeable implying that it comprises channels or poresallowing small particles with a diameter smaller than the pore size tofreely transport from the inside of the pouch to the exterior, or indeedvice versa. However, larger particles present in the pouch and having adiameter larger than the pore size become entrapped therein.

The pores or channels of the semi-permeable pouch and the size of themultiple alginate particles are selected so that the particles, at leastinitially before being placed in the oral cavity, generally cannot passthrough the semi-permeable membrane or net of the pouch. The solidparticles can therefore preferably have an average diameter in the rangefrom one or a few micrometers up to several millimeters, such as from 10μm to 10 mm and preferably from 100 μm to 5 mm. Note that above givenpreferred ranges of the particle size is the average particle diameter.In practical implementations the individual alginate particles may havedifferent diameters so that the multiple solid particles havedistribution of particle diameters around the average diameter.

The permeability of the semi-permeable pouch, i.e. its nominal porediameter, is therefore selected to be smaller than above mentionedpreferred average particle diameter but is still large enough to allowthe relevant biologically active substance to pass through the membraneor net of the pouch. As for the particle diameter, the pore size of thesemi-permeable pouch is an average pore size with individual porediameters distributed around this nominal pore size.

The solid particles can be formed using a single alginate type or amixture of multiple, i.e. at least two, different alginate types.Generally, the dissolution rate of the of the alginate particles andthereby the release rate of the biologically active substance containedin the alginate matrix is dependent on the viscosity and the molecularweight of the alginate. In other words, the higher molecular weight andthereby the higher the viscosity of the alginate the longer dissolutionrate upon contact with the moist mucous membrane in the oral cavity.

The molecular weight of the alginate can therefore be selected in orderto achieve a desired controlled release of the biologically activesubstance. Thus, if a very quick release and uptake of the biologicallyactive substance is desired, lower molecular weight alginates are usedas compared to an application where an extended, slower release anduptake of the active substance is advantageous.

The smaller alginate molecules achieving a fast dissolution hasgenerally an average molecular weight within a range from about 20 000g/mol to about 90 000 g/mol, e.g. from 30 000 g/mol to 90 000 g/mol,including from 30 000 g/mol to 50 000 g/mol and from 30 000 g/mol to 40000 g/mol. Such a low molecular weight alginate is sold under thetrademark PROTANAL® LFR 5/60 by FMC BioPolymer. PROTANAL® LFR 5/60 hasan average guluronic acid content of 65 to 75% and an average mannuronicacid content of 25 to 35%. This sodium alginate further has a viscosityof 300-700 mPas as measured in a 10% aqueous solution thereof at atemperature of 20° C. and at a shear rate of 20 rpm by use of aBrookfield viscometer with a spindle No. 2. Solid alginate particlesmade of, for instance, PROTANAL® LFR 5/60 can achieve a dissolution timeof a few minutes, possible up to about 10 minutes, when the oraldelivery product is being placed in the mouth of a human.

Correspondingly, a slower release is achieved with the high molecularweight alginates having a comparatively higher viscosity than theabove-exemplified low molecular weight alginates. Such alginates canhave an average molecular weight in the range from about 100 000 g/molto about 500 000 g/mol, preferably from 100 000 g/mol to 250 000 g/mol,such as from 100 000 g/mol to 200 000 g/mol, preferably from 125 000g/mol to 175 000 g/mol. A non-limiting example of a suitable alginatewithin these molecular weight ranges is PROTANAL® LF 10/60 marketed byFMC BioPolymer. PROTANAL® LF 10/60 is a sodium alginate having anaverage guluronic acid content of 40 to 45% and an average mannuronicacid content of 55 to 60%. The viscosity of the alginate is 20-70 mPasas measured in a 1% aqueous solution thereof at a temperature of 20° C.and at a shear rate of 20 rpm by use of a Brookfield viscometer with aspindle No. 2. Solid particles made of these high molecular weightalginates, such as PROTANAL® LF 10/60, and enclosed in thesemi-permeable pouch has a dissolution time of several tens of minuteswhen being placed in the mouth of a human subject.

Generally the dissolution time of PROTANAL® LF 10/60 particles andtherefore the uptake time of any active substance contained therein is2-3 times longer than the dissolution time and uptake time achieved byPROTANAL® LF 5/60 particles.

A further suitable alginate that can be used in the embodiments includesPROTANAL® LF 120, a sodium alginate having an average guluronic acidcontent of 35 to 45% and an average mannuronic acid content of 55 to65%. The viscosity of the alginate is 70-150 mPas as measured in a 1%aqueous solution thereof at a temperature of 20° C. and at a shear rateof 20 rpm by use of a Brookfield viscometer with a spindle No. 2.Generally the dissolution time of PROTANAL® LF 120 particles andtherefore the uptake time of any active substance contained therein is10-15 times longer than the dissolution time and uptake time achieved byPROTANAL® LF 5/60 particles.

It is anticipated by embodiments that a combination of multiple lowmolecular weight alginates, a combination of multiple high molecularweight alginates or a combination of at least one low molecular weightalginate and at least one high molecular weight alginate can be used inorder to achieve a desired controlled dissolution profile. For instanceand depending on the actual biologically active substance or substancesenclosed in the alginate particles, a first set of the multiple alginateparticles can be of a low molecular weight alginate to achieve a fastonset of the delivery of the biologically active substance. A second setof the multiple alginate particles are then instead made of a highmolecular weight alginate to thereby achieve an extended and prolongeddelivery of the biologically active substance. This may of course beextended even further by mixing more than two different types ofalginates. Thus, by mixing alginates of varying molecular weights indifferent proportions different dissolution profiles and therebydifferent administration profiles can be achieved.

FIG. 7 is a diagram illustrating the serum concentration of abiologically active substance over time in a subject having an oraldelivery product of the invention positioned in its oral cavity. Thecurve 40 illustrates the release of the biologically active substancefrom a low molecular weight alginate in the semi-permeable pouch,thereby achieving a resulting peak in serum concentration following afew minutes after the positioning of the oral delivery product in theoral cavity. The solid particles of a comparatively higher molecularweight alginate present a slower release of the biologically activesubstance, as is illustrated by the curve 42. The serum peakconcentration due to those particles in the product may occur severaltens of minutes later, such as 20-40 minutes after the insertion of thedelivery product in the mouth. Curve 44 is the resulting serumconcentration that is basically a sum of the two curves 40, 42. Thus, bymixing different alginate species a desired administration profile of abiologically active substance and desired serum concentration profilecan be tailored.

This combined usage of solid particles of different alginate species canalso be used for a combined delivery of multiple different biologicallyactive substances in a single oral delivery product. Thus, a firstbiologically active substance is entrapped in the matrix of a firstalginate species having a first average molecular weight. A secondbiologically active substance is then included in solid particles formedby a second alginate having a second average molecular weight. In such acase, following position of the oral delivery product in the mouth ofthe animal subject, the solid particles of the first alginate salt willdissolve more quickly than the particles of the second alginate. As aconsequence, the first biologically active substance is firstadministered to the subject, while the delivery of the second activesubstance is delayed and more prolonged due to the higher dissolutiontime of the second alginate. This may of course be used for the casewith more than two different biologically active substances and/or usingat least two different alginate salt species for a given biologicallyactive substance.

If substantially the same administration profile of two or morebiologically active substances that are to be co-administered isdesired, the biologically active substances can be included together inthe alginate particles. However, if it is advantageous, such as fromstability point of view, or that the biologically active substancesrequire different local environments, such as pH, a first biologicallyactive substance is included in a first set of solid particles of analginate salt. A second biologically active substance is correspondinglyincluded in the matrix of a second set of particles of the same alginatesalt.

The at least one biologically active substance comprised within thematrix of the alginate salt particles can be any biologically activesubstance that can be entrapped in the particles and which is to beadministered locally within the oral cavity or, preferably, systemicallythrough uptake by the mucous membrane in the mouth. The oral deliveryproduct is in particular advantageous in connection with sensitivesubstances susceptible to destruction or deterioration unless providedin a protected environment, requiring specific local environment forefficient delivery and/or cannot effectively be administered throughother administration routes.

The alginate salt particles form an internal matrix, in which the localenvironment can be accurately controlled during the manufacture of thesolid particles to achieve a desired matrix environment adapted for theparticular biologically active substance. For instance, certainsubstances are prone to oxidize when present in an oxygen richatmosphere. The alginates of the present embodiments effectively form anoxygen barrier thereby housing the sensitive substance in a low oxygenmatrix, achieving a longer shelf life of the product without any needfor compensating the oxidizing problem by adding more of thebiologically active substance or requiring the addition ofanti-oxidants.

Furthermore, some additives, such as color and flavoring agents, thatare usually included in oral delivery products can be quite reactive.Such additives can be provided, in the oral delivery product externalfrom the solid alginate particles, thereby being separate from thebiologically active substance. Alternatively, the additives can bepresent in some of the alginate particles, while other alginateparticles constitute the actual vehicles and carry the biologicallyactive substance. However, even by providing these additives in a sameaqueous solution as the biologically active substance and the alginateduring production of the solid particles, the reactivity of theadditives is strictly restricted once the alginate matrix is formed.Thus, even though additives and the biologically active substance arepresent within the same alginate particles, any deleterious reactionsbetween the additives and the active substance are significantlyreduced.

A controlled local matrix environment of the solid alginate particlescan also be achieved by including selected molecules or agents in theaqueous solution during the production of the particles. For instance,the aqueous solution can be a buffered aqueous solution having a targetacid, neutral or basic pH. When forming the solid particles, followingdrying, this buffer system will be entrapped within the alginate matrixtogether with the biologically active substance. This is particularadvantageous if the biologically active substance will be decomposed oris in an inactive form unless present within a controlled pH interval.Furthermore, some biologically active substances can be very hard totake up by the subject body once released unless a certain pH intervalis used. For instance, paracetamol or acetaminophen is very hard todissolve in aqueous solutions unless a basic pH is used, sometimesrequiring a pH of at least 11. A further example is nicotine, whichrequires a basic pH, such as between 8 and 9, for optimal uptake rate bythe mucous membrane.

The solid alginate salt particles of the oral delivery product thereforepreferably comprises a buffer system achieving a local pH that isselected to optimal or at least suitable in terms of stability, uptakeand administration rate for the biologically active substance. Preferredexamples of such buffer systems providing a basic pH include a phosphatebuffer system, such as sodium phosphate, potassium phosphate; acarbonate buffer system, such as sodium carbonate, sodium bicarbonate,potassium carbonate, potassium bicarbonate; sodium hydroxide, potassiumhydroxide, or any combination thereof.

The alginate particle matrices can also function as carrier matrix forbiologically active substances having other particular requirements interms of local environment. For instance, the anti-inflammatory drugdiclofenac is traditionally administered embedded in a polyethyleneglycol (PEG) aggregate as the diclofenac substance itself is reallyreactive and may otherwise irritate mucous membranes when administeredorally. The alginate particles can, in their internal matrix, embed suchPEG aggregates of diclofenac, thereby preserving the desired local PEGenvironment around the diclofenac molecules even in the alginatecarrier.

The alginate particles of the oral delivery product of the invention canadvantageously be used in connection with biologically active substancesthat are susceptible to destruction or deterioration in thegastrointestinal tract. Thus, by placing the oral delivery product inthe oral cavity of a subject, the alginate particles will, due to themoist environment, start to dissolve and release the contained activesubstance. The active substance may then be taken up systemicallythrough the mucous membrane in the mouth. Thus, an administration thatavoids the first-pass metabolism of the biologically active substance isachieved.

The biologically active substance can be a therapeutic ornon-therapeutic substance. Examples of the latter are biologicallyactive ingredients that are not generally considered as apharmaceutical, e.g. a naturopathic preparation. As an example of anon-pharmaceutical active ingredient a stimulant or a nutraceutical maybe mentioned, the latter generally defined as a substance that may beconsidered a food or part of a food and provides medical or healthbenefits, including the prevention and treatment of disease.

Other biologically active substances may have both a therapeutical andnon-therapeutical use.

Therapeutically active substances are administered by the oral deliveryproduct to treat or at least inhibit a disease or disorder against whichthe therapeutic substance is active. The substance and the oral deliveryproduct may also be used for preventing a disease by being administeredgenerally prior to any symptoms associated with the disease.

In order to illustrate how the oral delivery product may be used forvarious disorders, some non-limiting examples are given below:

The oral delivery product can be used to treat disorders in the stomach,where the substances are delivered from the “serum side” instead of fromthe gastric side or by uptake from the intestine and after liverpassage. Typical disorders of the stomach would be the acid-relatedsymptoms such as gastritis, ulcers, reflux or infections caused byHelicobacter pylori. The types of substances that can be used includeantimicrobial agents, histamine-2-receptor antagonists and proton pumpinhibitors. Because the oral delivery product can administer substanceswithout the need to swallow water as with compressed tablets, theembodiments are very useful for any medication where the patients'disorder render them unable to swallow and/or retain the medication inthe body. Typical disorders are stroke, migraine, acute cardiacconditions and patients with obstructed digestion channel, seasickness,nausea and other situations where water is not available or cannot beswallowed. Many different types of substances may be used, among theseCNS-acting substances such as serotonin receptor antagonists,prescription-free sea-sickness tablets and various anti-inflammatorysubstances.

Another disorder where the oral delivery technology described herein canbe used is obesity. Indeed, obese patients may be surgically treated(having parts of their stomach or the intestine removed) so as to reducethe absorption of substances from the gut. Delivery of medication by theoral delivery product that have their effects on the nervous systemwould be unaffected by the patents gastrointestinal operation history.An example of a type of substance that may be delivered in a filmformulation according to the invention is sibutramin.

One interesting group of substances comprises the peptides and proteins.Substances of this group can not easily be taken in via the mouth andinto the gut since they will be digested by enzymes, mainly proteasesand peptidases, present both in the stomach and the intestine. However,peptides and certain proteins may be taken up trough mucous tissue afterrelease from the oral delivery product since, in contrast to the gut,there is little peptidase activity in the mouth.

Since the drug-carrying alginate particles in the semi-permeable pouchand melting in the mouth, does not need to have any sugar additives anddoes not have to be swallowed it will be very suitable for oral diabetestherapy. Examples of suitable substance classes are the sulfoneurides,biguanid derivatives.

Patients that are very suitable candidates for delivery of substancesaccording to the embodiments are the elderly people and children. Boththese groups of patients are typically receiving more medication thanthe average and are often not able to self-medicate properly. Elderlypeople often get medication for sleep and for disorders typicallyassociated with the ageing process such as dementia, Parkinson'sdisease, Alzheimer's disease, anxiety, depression and deficiencies ofvitamins, nutrients and co-factors. The substance classes for thiscohort of patients include CNS-acting drugs, antimicrobial agents andlow molecular-weight cofactors.

Further examples of biologically active substances that can beadministered alone or in combinations by the oral delivery productinclude urinary incontinence agents, e.g. oxybutynin; antihistamines,e.g. dimenhydrinate, diphenhydramine, chlorpheniramine,dexchlorpheniramine maleate; analgesics, e.g. aspirin, codeine morphine,dihyromorphone, oxycodone, etc.; anti-inflammatory agents, e.g.naproxyn, diclofenac, indomethacin, ibuprofen, acetaminophen, aspirin,sulindac; gastrointenstinals and antiemetics, e.g. metoclopramide;anti-epileptics, e.g. phenytoin, meprobamate, nitrezepam; vadosidaltors,e.g. nifedipine, papaverine, diltiazem, nicardirine; antitussive agentsand expectorants, e.g. codein phosphate; anti-asthmatics, e.g.theophylline; anti-spasmodics, e.g. atropine, scopolamine; hormones,e.g. insulin; diuretics; e.g. eltacrymic acid bendrofluazide;anti-hypotensives, e.g. propranolol, clonidine; bronchodilators, e.g.albuterol, anti-inflammatory steroids, e.g. hydrocortisone,triamcinolone, prednisone; antibiotics, e.g. tetracycline,antihemmorrhoidals; anitdiarrheals; mucolytics; sedatives;decongestants; laxatives; antacids, etc.

The oral delivery product is in particular suitable for comprising anicotine (3-(1-methyl-2-pyrrolidinyl)-pyridine) substance asbiologically active substance. This includes synthetic nicotine andnicotine extracts from tobacco plants, such as the genus Nicotiana,nicotine base, nicotine hydrochloride, nicotine dihydrochloride,nicotine monotartrate, nicotine bitartrate, nicotine sulphate, nicotinezinc chloride (monohydrate) and nicotine salicylate. Furthermore, otheralkaloids with the same direction of activity including nornicotine andlobeline, e.g. of the species Lobeliaceae and Lobelia, methylanabasine,anabasine can alternative be used.

In addition to being used in smoking curing, the oral delivery productcomprising nicotine as biologically active substance can be used as asubstitute for wet snuff mainly seen today in the U.S. and Scandinavia.Although wet snuff is generally not implicated in the cardiovascular andlung disease morbidity and mortality caused by smoking, the content ofnitrosamines in snuff poses a potential hazard for some cancer diseases.It is therefore of interest to make available to consumers a snuff-likeproduct while minimizing this potential hazard.

The oral delivery product comprising the multiple solid alginateparticles with nicotine in the semi-permeable pouch effectively meetsthe above mentioned objectives. The product has the further advantagethat it can use the same semi-permeable pouch material and size that istraditionally used in pre-baked snuff pouches or bags. Thus, thephysical feeling the snuffer gets when placing the oral delivery productunder the lip is substantially the same as when placing a snuff pouch.

The oral delivery product comprising nicotine as biologically activeagent has further advantages when being used instead of a traditionaltobacco-containing snuff product. Alginates have scientifically provenproperties in promoting wound healing, and soothing and alleviating skinirritations. People regularly using snuff products have an increasedrisk of irritation to the mucous membranes under the lip, possibly evenleading to open wounds. Using the oral delivery agent of the invention,the alginates dissolving from the alginate particles will promote woundhealing and soothe the irritations caused by the prior art snuffproducts.

Further examples of active substances that can be used according to theembodiments include caffeine, vitamin B12, vitamin C, vitamin E,Bioperine® (extract from the fruit of Piper Nigrum L or Piper longum Land contains a high percentage of piperine), Coenzyme Q10, selenium,glutathione, alpha lipoic acid (ALA), folic acid, ginseng, antioxidants,minerals, paracetamol and acetylsalicylic acid.

The alginate particles may also, in particular when the active substanceis nicotine, comprise tobacco, typically a small amount of tobacco addedfor providing a desired flavour that mimics the one of traditional snuffproducts.

FIG. 1A is a view from above of an example of an oral delivery product 1according to an embodiment. The oral delivery product comprises thesemi-permeable pouch 10 filled with the alginate particles 20. In thefigure, the reference number 14 indicates a pore or channel of the pouch10, allowing passage of the biologically active substance, such asnicotine, through the pouch wall or net. The pouch 10 is generallysealed in the short ends 12 thereof, entrapping the alginate particles20 in the formed pouch chamber. Sealing can be used according to varioustechniques, which are all well-known today within the snuff pouchproducing industry. A non-limiting example of sealing technique is heatsealing. FIG. 1B is a side view of the oral delivery product 1.

The solid particles of the alginate salt may comprise up to 85% byweight of the total formulation of the at least one biologically activesubstance, such as up to 70% by weight, or up to 60% by weight, such as5 to 60% by weight, preferably 5 to 50% by weight, or 10 to 40% byweight. It should however be understood that it is also contemplatedthat the alginate formulation may contain very low levels of thebiologically active substance, if this for any reason is desired, e.g.if the active substance is to be delivered at a very small dosage. Thus,if preferably, the alginate particles may contain the at least onebiologically active substance at a very low level, e.g. as low as0.000001% by weight.

The semi-permeable pouch may also, in addition to the alginateparticles, comprise excipients or additives, such as filler particles ofa filler material. An example of suitable filler material is cellulose,such as microcrystalline cellulose. Such microcrystalline cellulose canform particles having varying particle diameters. In such a case, theabove-suggested diameter ranges for the alginate particles are also ofrelevance for the microcrystalline cellulose particles. AVICEL® PH-200is an example of a microcrystalline cellulose having a suitable averageparticle size of 180 μm diameter. Other cellulose particles can beselected from AVICEL® PH-100, PH-102, PH-103, PH-105, PH-112, PH-113,PH-300, PH-302, VIVACEL® grades 101, 102, 12, 20 and EMOCEL® grades 50Mand 90M and mixtures thereof.

With reference to FIG. 2, in a typical embodiment the semi-permeablepouch 10 encloses from about 1 to 100% by weight of the alginateparticles 20 and 0 to 99% by weight of the filler particles 30,preferably 5 to 75% by weight of the alginate particles 20 and 25 to 95%by weight of the filler particles 30, such as 5 to 50% by weight of thealginate particles 20 and 50 to 95% by weight of the filler particles30, and more preferably 10 to 30% by weight of the alginate particles 20and 70 to 90% by weight of the filler particles 30.

The optional filler material can be used as passive filler material ormay indeed be used as an additional substance carrier. In the lattercase, the at least one biologically active substance enclosed by thealginate particles 20 and/or another biologically active substance canbe sorbed onto the surface of the filler particles 30. Microcrystallinecellulose particles 30 are generally highly porous particles 30 with alarge part thereof being voids and pores. In such a case, thebiologically active substance, such as nicotine, can be absorbed oradsorbed to the cellulose surface in the many voids and pores, therebyachieving a very large sorbtion surface. WO 2007/104573 discloses suchmicrocrystalline cellulose particles 30 with sorbed nicotine. Theteaching of that patent document as far as relating to nicotine-carryingcellulose particles 30 is hereby incorporated by reference for usage asan active filler material. Such active filler materials carrying abiologically surface, can be used to achieve a very fast onset of thesubstance delivery that can occur before or at least partly overlappingthe delivery from light molecular weight alginate particles 20.

A further example of additive that can be used in the oral deliveryproduct is at least one plasticizer, preferably comprised in the solidparticles of the alginate salt of monovalent cation. The plasticizer,when present, may be selected from e.g. polyethylene glycols, glyceroland sorbitol. A preferred plasticizer is sorbitol optionally togetherwith a small part of glycerol. A suitable amount of plasticizer is e.g.from 1 to 85 g, such as from 5 to 70 g or from 10 to 70 g, e.g. from 30to 70 g, or from 40 to 70 g, including from 50 to 60 g of plasticizerper 100 g of alginate.

Further physiologically, i.e. non-toxic at the added level, and/orpharmacologically acceptable additives include one or more flavouringagents, such as taste maskers, and/or colouring agents. Examples offlavouring agents are essential oils including distillations, solventextractions or cold expressions of chopped flowers, leaves, peel orpulped whole fruit comprising mixtures of alcohols, esters, aldehydesand lactones. Essences including either diluted solutions of essentialoils or mixtures of synthetic chemical blends to match the desiredflavour of the fruit, e.g. strawberry, raspberry, cranberry, orange,lemon, lime, cherry and black current can also be used. Further examplesinclude artificial and natural flavours of brews and liquors, e.g.cognac, whiskey, rum, gin, sherry, port, and wine; tobacco, coffee, tea,cacao, mint, peppermint, eucalyptus, liquorice, and menthol.

Sweeteners, such as sorbitol, xylitol, maltitol, isomalt, aspartame,acesulfame, saccharin, sucrose, glucose, fructose, lactose, mannitol,etc., can also or in addition be added to the gum.

According to an embodiment colouring additives can be selected from dyescontaining chemical groups which absorb light including dyes, such astartrazine, indigo carmine, amaranth, erythrosine, carbon black,titanium dioxide and any mixtures thereof.

The sweeteners, flavouring and colouring agents, if included, may bepresent from about 0.075% w/w to about 35% w/w, such as from about0.075% w/w to about 5% w/w.

Even though generally not necessary for the storage and efficientdelivery of the biologically active substance from the oral deliveryproduct, further additives selected from binders, wetting agents,stabilizing agents, surface active agents, absorption enhancers,texture-improving agents and anti-oxidant may optionally be included inthe oral delivery product, preferably by being comprised in the matrixdefined by the alginate salt of monovalent cation.

FIG. 3 is a flow diagram illustrating an embodiment of producing an oraldelivery product according to an embodiment. The method generally startsin step S1, which forms multiple solid particles from an aqueoussolution of at least one alginate salt of monovalent cation and at leastone biologically active substance. The at least one active substance isfurther contained within the matrices of the multiple particles formedby the at least one alginate salt. A next step S2 fills a semi-permeablepouch designed for being placed in the oral cavity of an animal subject,preferably human subject and more preferably under the lip of the humansubject, with the formed solid alginate particles. The so filled pouchis then enclosed and sealed thereby obtaining the oral delivery product.

If any filler particles are to be used, they are of course filled in thesemi-permeable pouch prior to the sealing thereof.

FIG. 4 is a flow diagram illustrating additional steps of the producingmethod in FIG. 3. The method starts in step S10, where the at least onealginate salt of monovalent cation is added to an aqueous solution,preferably a buffered aqueous solution of the at least one biologicallyactive substance. In an alternative embodiment, the biologically activesubstance is instead added to an, preferably buffered, aqueous solutionof the at least one alginate salt.

Any additives, such as plasticizers, flavoring agents, coloring agents,are preferably added to the solution prior to the addition of thealginate salt, though a subsequent addition of the additives is indeedfeasible.

A next step S11 stirs the mixture to form a homogenous solution.Optionally mild heating, such as up to 60° C., preferably no more thanup to 50° C. or 40° C., may be applied during the stirring operation.The method then continues to step S1 of FIG. 3.

FIG. 5 is a flow diagram illustrating an embodiment of the particleforming step S1 in FIG. 3. In this embodiment, the solid alginateparticles are formed by subjecting the (buffered) aqueous solution to afreeze granulation process. Generally, the freeze granulation process isa two-step process. The first step S20 involves spray freezing theaqueous alginate and substance solution into a cooling liquid, such asliquid N₂, to form frozen granulates. The frozen alginate granulates ofwith the biologically active substance are then subject to freezedrying, such as at a temperature of about −10° C. to −60° C., such asabout −40° C., to form the multiple solid alginate particles carryingthe biologically active substance in their matrices. Freeze granulationhas several production advantages, such as allowing formation of a widerange of particle diameters and providing tight control of the granuledensity. Furthermore, the mild drying provides a low degree of oxidationand is therefore suitable for substances sensitive for oxidation.

Appliances for performing freeze granulation, even in a large-scale, aretoday available on the market, such as from PowderPro Goteborg AB.

If multiple different alginate particles are to be used they may all bemixed in the same aqueous solution so that the solid particles formed bythe freeze granulation processes are a mixture of the alginatemolecules.

Alternatively, multiple separate aqueous solutions comprising differentalginates or different alginate mixtures can individually be subject tothe freeze granulation. In such a case, solid alginate particles ofdifferent alginate species are obtained.

FIG. 6 is a flow diagram illustrating another embodiment of forming thesolid alginate particles in step S1 of FIG. 3. The method continues fromstep S11 of FIG. 4. A next step S30 dries the aqueous solutioncomprising the alginate salt, the at least one biologically activesubstance, preferably the buffering agent or agents and optionally otheradditives and excipients. Drying is preferably performed at roomtemperature, e.g. 17-25° C., and under a normal atmosphere for a timeperiod required to form one or more solid bodies.

Drying may also be performed under a dry atmosphere or under a lowerthan atmospheric pressure in order to speed up the drying process. Inthe case the biologically active substance is not susceptible to thermaldegradation, drying may be further accelerated by raising thetemperature, such as to about 35° C. Drying may also be accelerated bydistributing the solution onto a solid surface and allowing to dry intoa solid body.

The one or more solid bodies formed following the drying process in stepS30 is then cut or ground into small solid alginate particles having adesired particle size. An optional sorting process can be conducted bysorting the formed alginate particles based on particle diameter indifferent meshes. The method then continues to step S2, where thealginate particles are packet in the pouch.

If multiple alginate species are to be used, a first implementation runsthe method in steps S30-S31 individually for each alginate (mixture)solved in its dedicated aqueous solution. The resulting solid particlesare then mixed together prior before being filled in the pouch. In asecond implementation, a single aqueous solution comprises a mixture ofdifferent alginates are formed, dried and then cut into small solidparticles.

EXAMPLES Example 1

A buffered aqueous solution comprising paracetamol as activepharmaceutical ingredient can be made with the following ingredients:

10 g sodium alginate corresponding to PROTANAL® LFR 5/60;

80 g distilled water;

3 g sorbitol;

2 g glycerol;

2 g cranberry extract;

1 dropgreen food colour;

-   -   sodium hydroxide;

5 g paracetamol.

The active pharmaceutical ingredient is mixed with water and the pHadjusted to about 8-8.5 by addition of aqueous NaOH. The plasticizers,flavouring and colouring agents are added. The PROTANAL® LFR 5/60 isthen added to the above-mentioned aqueous solution at room temperaturein small portions and mixed until a homogenous solution is obtained.

The solution is allowed to dry at room temperature at atmosphericpressure until a sold is formed. The solid is ground into small alginateparticles having an average diameter size of 200-500 μm.

Example 2

The proceeding generally as in EXAMPLE 1, alginate particles areprepared by the use of the following ingredients:

12 g sodium alginate corresponding to PROTANAL® LFR 5/60;

80 g distilled water;

3 g sorbitol;

2 g glycerol;

2 g cranberry extract;

1 dropgreen food colour;

-   -   sodium hydroxide;

12 g paracetamol.

Example 3

An alginate formulation is prepared by use of the following ingredients:

12 g sodium alginate corresponding to PROTANAL® LFR 5/60;

80 g distilled water;

3 g sorbitol;

2 g glycerol;

2 g cranberry extract;

1 dropgreen food colour;

6 g ibuprofen dissolved in ethanol.

The active pharmaceutical ingredient, ibuprofen, is dissolved in a smallvolume of ethanol and the solution is mixed with water, resulting inprecipitation of ibuprofen crystals. The plasticizers, flavouring andcolouring agents are added. PROTANAL® LFR 5/60 is then added, at roomtemperature in small portions and mixed until a homogenous milky whitesuspension of ibuprofen crystals is obtained. The suspension is dried atroom temperature at atmospheric pressure, giving a solid that can be cutor ground into solid particles of a target size distribution.

Example 4

Proceeding generally as in EXAMPLE 1, but using aqueous bicarbonatebuffer to regulate the pH of the composition:

12 g sodium alginate corresponding to PROTANAL® LFR 5/60;

80 g aqueous sodium bicarbonate buffer pH 8-8.5;

3 g sorbitol;

2 g glycerol;

2 g cranberry extract;

1 drop green food colour;

5 g acetylsalicylic acid.

Example 5

Proceeding generally as in EXAMPLE 1, a formulation is prepared by useof the following ingredients:

12 g sodium alginate corresponding to PROTANAL® LFR 5/60;

80 g distilled water;

2 g cranberry extract;

-   -   sodium hydroxide;

12 g paracetamol.

Example 6

An alginate formulation is prepared by use of the following ingredients:

11 g sodium alginate corresponding to PROTANAL® LFR 5/60;

80 g aqueous potassium phosphate buffer pH 8.5, 0.1 M;

2 g glycerol;

3 g sorbitol;

5.5 g nicotine bitartrate.

The active ingredient, nicotine bitartrate, is mixed with the buffer.Glycerol and sorbitol are added. The PRONATAL® LFR 5/60 is then added tothe thus prepared aqueous solution at room temperature in small portionsand mixed until a homogenous solution is obtained.

The solution is allowed to dry at room temperature at atmosphericpressure.

Example 7

An alginate formulation is prepared by use of the following ingredients:

10 g sodium alginate corresponding to PROTANAL® LF 10/60;

150 g aqueous potassium phosphate buffer pH 8.5, 0.1 M;

2 g glycerol;

3 g sorbitol;

5.5 g nicotine bitartrate.

The active ingredient, nicotine bitartrate, is mixed with the buffer.Glycerol and sorbitol are added. The PRONATAL® LF 10/60 is then added tothe thus prepared aqueous solution at room temperature in small portionsand mixed until a homogenous solution is obtained.

The solution is allowed to dry at room temperature at atmosphericpressure.

Example 8

An alginate formulation is prepared by use of the following ingredients:

6 g sodium alginate corresponding to PROTANAL® LFR 5/60;

4 g sodium alginate corresponding to PROTANAL® LF 10/60;

150 g aqueous potassium phosphate buffer pH 8.5, 0.1 M;

2 g glycerol;

3 g sorbitol;

5.5 g nicotine bitartrate.

The active ingredient, nicotine bitartrate, is mixed with the buffer.Glycerol and sorbitol are added. The PRONATAL® LFR 5/60 and LF 10/60 arethen added to the thus prepared aqueous solution at room temperature insmall portions and mixed until a homogenous solution is obtained.

The solution is allowed to dry at room temperature at atmosphericpressure.

Example 9

The proceeding generally as in EXAMPLE 1, alginate particles areprepared by the use of the following ingredients:

10 g sodium alginate corresponding to PROTANAL® LFR 5/60;

80 g distilled water;

4 g sorbitol;

3 g glycerol;

4 g 1% (w/w) powder of vitamin B12—the reminder being tablet fillermaterial.

The alginate particles formed according to any of the above listedexamples are then filled in a semi-permeable pouch that is being sealed,preferably by heat sealing, to form an oral delivery product. Filling ofthe pouch with the particle and sealing thereof can be conducted usingconventional techniques, e.g. used in the snuff industry today.

It will be understood by a person skilled in the art that variousmodifications and changes may be made to the present invention withoutdeparture from the scope thereof, which is defined by the appendedclaims.

1. An oral delivery product comprising: a semi-permeable pouch designedfor placement in an oral cavity of a subject; and multiple solidparticles of at least one alginate salt of monovalent cation, whereinsaid multiple solid particles (i) comprise at least one biologicallyactive substance within a matrix formed by said at least one alginatesalt of monovalent cation, (ii) are dissolvable in the moist environmentof the oral cavity, and (iii) are enclosed in said semi-permeable pouch.2. The product according to claim 1, further comprising filler particlesof a filler material.
 3. The product according to claim 2, wherein saidfiller particles are microcrystalline cellulose particles.
 4. Theproduct according to claim 3, wherein said microcrystalline celluloseparticles have sorbed an amount of said at least one biologically activesubstance in voids and pores within said microcrystalline cellulose. 5.The product according to claim 3, wherein said semi-permeable pouchencloses 10 to 30% by weight of said multiple solid particles and 70 to90% by weight of said filler particles.
 6. The product according toclaim 1, wherein said multiple solid particles of said at least onealginate salt of monovalent cation further comprises at least oneplasticizer.
 7. The product according to claim 1, wherein said multiplesolid particles of said at least one alginate salt of monovalent cationfurther comprises a buffer system within said matrix.
 8. The productaccording to claim 7, wherein said buffer system provides a basic pH tosaid multiple solid particles and is selected from a phosphate buffersystem or a carbonate buffer system.
 9. The product according to claim1, wherein said monovalent cation is selected from Na⁺, K⁺ and NH₄ ⁺.10. The product according to claim 1, wherein said multiple solidparticles of said at least one alginate salt of monovalent cationcomprise said at least one biologically active substance at a level offrom 0.000001 to 85% by weight of a total weight of said multiple solidparticles.
 11. The product according to claim 1, wherein said at leastone biologically active substance is nicotine.
 12. The product accordingto claim 1, wherein said multiple solid particles of said at least onealginate salt of monovalent cation comprise: a first set of multiplesolid particles of a first alginate salt of monovalent cation comprisingsaid at least one biologically active substance within a matrix formedby said first alginate salt of monovalent cation, said first alginatesalt having a first average molecular weight; and a second set ofmultiple solid particles of a second alginate salt of monovalent cationcomprising said at least one biologically active substance within amatrix formed by said second alginate salt of monovalent cation, saidsecond alginate salt having a second average molecular weight that iscomparatively larger than said first average molecular weight.
 13. Theproduct according to claim 12, wherein said first average molecularweight is within a first range of from 30,000 g/mol to 90,000 g/mol andsaid second average molecular weight is within a second range of from100,000 g/mol to 500,000 g/mol.
 14. The product according to claim 12,wherein said first alginate salt is an alginate salt of monovalentcation having a guluronic acid content of 65 mole % to 75 mole % and amannuronic acid content of 25 mole % to 35 mole % and a 10% aqueoussolution thereof at a temperature of 20° C. has a viscosity of 300-700mPas as measured at a shear rate of 20 rpm by use of a Brookfieldviscometer with a spindle No.
 2. 15. The product according to claim 12,wherein said second alginate salt is an alginate salt of monovalentcation having a guluronic acid content of 40 mole % to 45 mole % and amannuronic acid content of 55 mole % to 60 mole % and a 1% aqueoussolution thereof at a temperature of 20° C. has a viscosity of 20-70mPas as measured at a shear rate of 20 rpm by use of a Brookfieldviscometer with a spindle No.
 2. 16. The product according to claim 12,wherein said first alginate salt of monovalent cation and said secondalginate salt of monovalent cation have different rates of dissolutionin the moist environment of the oral cavity.
 17. A method of producingan oral delivery product according to claim 1, comprising: formingmultiple solid particles from an aqueous solution of at least onealginate salt of monovalent cation and at least one biologically activesubstance, wherein said at least one biologically active substance iscontained within a matrix formed by said at least one alginate salt ofmonovalent cation; and enclosing said multiple solid particles in asemi-permeable pouch designed for placement in an oral cavity of asubject.
 18. A method of inhibiting or preventing a disease comprisingpositioning, in an oral cavity of a subject suffering from said disease,an oral delivery product according to claim 1 comprising asemi-permeable pouch designed for placement in said oral cavity andenclosing multiple solid particle of at least one alginate salt ofmonovalent cation, said multiple solid particles comprising at least onepharmaceutically active substance within a matrix formed by said atleast one alginate salt of monovalent cation, said pharmaceuticallyactive substance being capable of inhibiting or preventing said disease.